Biochemical Pharmacology

Phospholipids are building blocks of the cell membranes, but phospholipids are also precursors for intercellular and intracellular signalling molecules that function as local hormones (autocoids) and as second messengers, respectively. Some of these bioactive lipids (e.g. eicosanoids) are formed from arachidonic acid, which again is formed from dietary linoleic acid. Both of these fatty acids have essential functions in mammals. Fish oils contain long-chain n-3 fatty acids, which can affect arachidonic acid metabolism, affect gene expression and affect membrane microdomains (rafts), and the dietary intake of n-3 fatty acids can thus affect different biological parameters. Furthermore, dietary n-3 fatty acids are essential for the development of the brain and the retina.

Other bioactive lipids comprise diacylglycerol, phosphatidic acid, platelet activating factor, lyso-phosphatidic acid, ceramide, sphingosine-1-phosphate, phosphatidylinositol 3,4,5-trisphosphate, non-esterified fatty acids, oleamide, 2-arachidonoyl-glycerol, anandamide , N-oleoylethanolamine and other N-acyl-ethanolamines. We are interested in understanding where, how, and when these bioactive lipids are formed.

We are currently focusing on understanding the biological functions of N-acyl-ethanolamine phospholipids (NAPE) and of N-acyl-ethanolamines (NAE) in the brain and in other tissues. We are characterising the enzymes involved in the formation of NAPE (N-acyl-transferase) and in the formation of NAE (NAPE-hydrolysing phospholipase D), and measuring endogenous levels og NAPE and NAE.

NAPE and NAE can be formed in high amounts in cultured neurons exposed to excitotoxic concentrations of glutamate or other compounds, which can induce cell injury. NAPE is believed to have a membrane stabilizing effect, and NAPE is formed as a stress response in cultured neurons. Some molecular species of NAE, e.g. N-arachidonoyl-ethanolamine (also called anandamide) is a ligand for cannabinoid receptors and vanilloid receptor. N-Arachidonoyl-ethanolamine has the same biological effects as D⁹-tetra-hydrocannabinol, and N-palmitoyl-ethanolamine has antinociceptive and antiinflammatory effects mediated by unknown mechanisms, some of them probably via PPARa. N-Oleoylethanolamine can inhibit food intake via activation of PPARa and/or via the orphan receptor GPCR119. The signal is transmitted from the intestine where the receptors via vagus c-fibers to the appetite centre of the brain.

2-Arachidonoyl-glycerol, which can be formed during inositol phospholipid turnover, is also a ligand for the cannabinoid receptors. 2-Arachidonoyl-glycerol and anandamide are considered as endocannabinoids and they are suggested to be involved in retrograde communication in glutaminergic and GABAergic synapses.

We have found that these lipids are also elevated in human brain tumours where they are assumed to have a growth-inhibiting effect. Furthermore, we collaborate with others about the significance of these lipids in animal models of epilepsy and brain ischemia, in regulation of food intake, and in adipose tissue lipolysis.